Vitamin E (d-alpha-tocopherol, 1) is an important nutritional supplement in humans and animals. Compound 1 is obtained commercially by isolation from a variety of plant oils, or semi-synthetically by ring methylation of the related naturally occurring d-gamma-tocopherol 2. A more important source of vitamin E is total synthesis, which provides synthetic vitamin E, d,1-alpha-tocopherol, 3. Although a mixture of isomers, 3 provides much of the biological activity of 1 and is widely used due to its lower cost and greater availability. For a general discussion of vitamin E, see L. Machlin, ed., "Vitamin E: A Comprehensive Treatise", Marcel Dekker, NY, 1980. ##STR1##
The mixture of isomers comprising synthetic vitamin E, d,1-alpha-Tocopherol 3, is typically obtained by reacting trimethylhydroquinone 4 with either phytol 5 or isophytol 6 in the presence of an acid catalyst, often a Lewis acid such as zinc chloride. ##STR2##
This technology was reviewed by S. Kasparek in L. Machlin, ed., Vitamin E: A Comprehensive Treatise, chapter 2, pp. 8-65, Marcel Dekker, NY, 1965. References 140-166 of this chapter provide the primary references to detailed methods of preparing compound 3.
The phytol 5 or isophytol 6 required for the prior art preparations of 3 have typically been obtained through multi-step synthesis. Starting materials typically included acetone (see Kasparek, in Machlin, Vitamin E: A Comprehensive Treatise, pp. 44-45, Dekker, NY 1980, and references cited therein) and cyclic isoprene trimer (Pond et al., U.S. Pat. Nos. 3,917,710 and 3,862,988 (1975).
One embodiment of the present invention relates to methods for preparing phytol, isophytol, certain substituted derivatives thereof, and vitamin E, starting from geranylgeraniol 7. ##STR3##
Geranylgeraniol can be derived from plant or microbial sources, but at high cost. More economical techniques for production and isolation of geranylgeraniol can be provided by modem biotechnology, as disclosed in U.S. Provisional Application Ser. No. 60/091,686, incorporated herein by reference.
The present invention further relates to certain C.sub.20 epoxide derivatives, such as 2,3-epoxygeranylgeraniol, 8, 2,3-epoxyphytol 9, and 1,2-epoxyisophytol, 10. Compounds 8, 9, and 10 are known (Sata et.al., Tetrahedron Letters 1999, 40(4) 719-722; ##STR4## and Sato et.al, JP 63063674, A2 880302; Rontani et.al., Phytochemistry, 1996, 42(2), 347-351; Aliya et.al, Pak J. Mar. Sci. 1994, 3(1), 15-24; Rontani et.al., J. Photochem. Photobiol. A 1994, 79(3), 167-172; Kanehira et.al., JP 63179850 A2 880723;).
Methods are also known in the art for selectively epoxidizing the carbon--carbon double bond of allylic alcohols in the presence of other carbon--carbon double bonds, by utilizing t-butyl-hydroperoxide in the presence of molybdenum or vanadium catalysts (Sharpless et.al., J.Amer.Chem.Soc. 1973, 95,6136-6137). Those methods have been applied to synthesize 1,2-epoxyisophytol, 10, from isophytol, 6 (Mori et.al., abstract of JP 61236737 A2 861022)
In the last few years, a rhenium compound, CH.sub.3 ReO.sub.3, methyl rhenium trioxide, 11, has been shown to be a useful catalyst for a variety of transformations of organic compounds, as reviewed by Schmidt (J. Prakt. Chem./Chem Ztg. 1997, 339, 493-496). The types of reactions catalyzed by CH.sub.3 ReO.sub.3 include the isomerization and/or equilibration of allylic alcohols such as phytol (U.S. Pat. No. 5,349,097 to Tome et.al.), the dehydration of primary alcohols to give ethers and olefins (Zhu and Espenson, J.Org. Chem. 1996, 61, 324-328) and the deoxygenation of epoxides in the presence of oxygen acceptors to give olefins (Zhu and Espenson, J. Mol. Catalysis A: Chemical 1995, 103, 87-94).
Despite the various known methods for preparing or isolating members of the vitamin E family of compounds and their precursors, there remains a need for improved and more efficient methods of production of phytol, isophytol, and Vitamin E. It would be especially useful to chemically convert geranylgeraniol 7 to phytol 5, isophytol 6, vitamin E, or related compounds.